Chronic inflammation produced by cigarette smoking may contribute to the development of emphysema by promoting elastin degradation, and also by influencing the repair of damaged elastin. The influence of chronic inflammation on the repair process may in part be mediated by transforming growth factor-beta (TGF-Beta). Pulmonary macrophages may play a central role in modulating the effects of TGF-Beta in the pulmonary interstitium by secreting this growth factor and activating TGF-Beta which has been produced by other cells. Preliminary studies have shown that TGF-Beta elicits a 2-fold increase in tropoelastin (TE) production by cultured neonatal and adult rat lung fibroblasts. This increase is reflected by a similar elevation in the steady-state levels of elastin mRNA. The capability of TGF-Beta to limit the proteolytic degradation of newly synthesized TE will be examined by characterizing the effects of TGF-Beta on the production of proteinases and proteinase inhibitors by rat lung fibroblasts. Alterations in elastin gene expression mediated by TGF-Beta will be further characterized by translation of isolated poly A-RNA in vitro, by examining the rate of transcription of the elastin gene using isolated nuclei, and by analyzing the stability of elastin mRNA. Preliminary experiments have shown that normal human and hamster alveolar macrophages and normal hamster interstitial macrophages secrete TGF-beta. The production and secretion of TGF-Beta by alveolar and interstitial pulmonary macrophages will be examined to determine whether inflammation associated with cigarette smoking or intratracheal instillation of carbon particles into hamsters may increase the secretion and biologic activity of TGF-Beta. The production and secretion of TGF-Beta by rat lung fibroblasts will also be examined as preliminary data suggest that TGF-Beta may influence elastin production by these cells through an autocrine mechanism. Interactions between co-cultured pulmonary fibroblasts and macrophages will be analyzed to determine whether these interactions may promote the activation of TGF-Beta that has been secreted by these cells and to characterize the mechanisms responsible for this promotion. The role of plasmin generation in this process will be examined in detail. A better understanding of the potential role of TGF-Beta in the synthesis of elastin in the pulmonary interstitium, may ultimately contribute to the development of therapies that could promote the repair of elastin in emphysematous human lungs.